Acquired Immunodeficiency Syndrome (AIDS) was coined in 1982 to describe the clinical manifestations of immunodeficiency. The etiological agent of AIDS was later associated with a retrovirus, Human Immunodeficiency Virus (HIV), from the lentivirus subfamily. At least two infectious strains of HIV have been identified, HIV-1 and HIV-2. Here, HIV will be used as a general term describing all strains and mutants of the Human Immunodeficiency Virus. The detailed study of HIV has given rise to many approaches to antiviral drug development including inhibition of the viral aspartyl protease (D. Richman, Control of Virus Diseases, 45th Symposium of the Society for General Microbiology, 261-313 (1990)).
Aspartyl proteases have been found in many retroviruses including the Feline Immunodeficiency Virus (FIV), the Myeloblastosis Associated Virus (MAV), HIV, and the Rous Sarcoma Virus (RSV) H. Toh et al., Nature, 315: 691 (1985); J. Kay, B. M. Dunn, Biochim. Biophys. Acta, 1: 1048 (1990); C. Cameron et al., J. Biological Chem., 168: 11711-720 (1993)!. Since there are structural similarities among the known retroviral proteases, compounds which inhibit the HIV protease may well inhibit other retroviral proteases and thus be useful in the treatment of diseases caused by these viruses.
HIV aspartyl protease is responsible for post-translational processing of viral precursor polyproteins such as pol and gag. (M. Graves, Structure and Function of the Aspartic Proteases, 395-405 (1991)). Cleavage of these polyproteins by this protease is essential for maturation of the virus, since the proteolytic activity necessary for polyprotein processing cannot be provided by host cellular enzymes. An important finding has been that viruses which lack this protease, or contain a mutation which produces a defective protease, lack infectivity C. Peng et al., J. Virol, 63: 2550-2556 (1989); and N. Kohl et al., Proc. Nati. Acad. Sci. USA, 85: 4686-4690 (1987)!. Thus, a selective HIV protease inhibitor has been shown to inhibit viral spread and the production of association cytopathic effects in cultures of acutely infected cells (J. C. Craig et al., Antiviral Research, 16: 295-305 (1991)). For this reason, inhibition of HIV protease is believed to be a viable approach to antiviral therapy.
HIV protease inhibitors have been extensively reviewed (see for example A. Tomasell et al., Chimica Oggi, 6-27 (1991) and T. Meek, J. Enzyme Inhibition 6: 65-98 (1992)). However, the majority of these inhibitors are peptides and thus unsuitable as drugs, due to the well known pharmacological deficiencies exhibited by most peptide drugs (biliary excretion, low-bioavailability and stability in physiological milieu, etc.). Nonpeptidic inhibitors of HIV protease are thus very important, since these may lead to useful therapeutic agents.
Hei 3-227923 claimed coumarins with anti-HIV activity. However, only 4-hydroxycoumarin was specifically described without discussion of mechanism of action.
World Patent 89/07939 claimed eight coumarin derivatives as HIV reverse transcriptase inhibitors with potential antiviral activity. These derivatives are hexachlorocoumarin, 7-acetoxycoumarin, and the structures shown below. ##STR1##
Warfarin (3-(.alpha.-acetonylbenzyl)-4-hydroxycoumarin), shown below, was reported by R. Nagorny et al. in AIDS 7: 129-130 (1993) as inhibiting cell-free and cell-mediated HIV infection. However, Warfarin was the only pyrone studied and its mechanism of action in HIV inhibition was not specified. ##STR2##
Selected flavones, structurally different from the pyrones of the present invention, were reported by Fairli et al., (Biochem. Biophys. Res. Comm., 188: 631-637 (1992)) to be inhibitors of HIV-1 protease. These compounds are shown below. ##STR3##
U.S. Pat. No. 3,206,476 describes several pyrones, specifically 3-substituted-4-hydroxy-6-aryl-2-pyrones, as antihypertensive agents. However, the range of substituents at the 3-position of these heterocycles is limited to halo and amino groups and alkanoylamino derivatives.
U.S. Pat. No. 3,818,046 describes several pyrone derivatives, specifically 4-hydroxypyrones with sulfur-containing carbon chains at the 3-position, as growth stunters and antimicrobial agents.
These pyrones, which are shown below, are substituted as follows: R=Me, M=H or alkali metal; R'=H, alkyl, phenyl, halophenyl, nitrophenyl, lower alkylphenyl, benzyl, phenethyl, naphthylmethyl, halobenzyl, lower alkylbenzyl, nitrobenzyl, propargyl, allyl, cyclohexyl lower alkyl, lower alkylthio, or adamantyl; and n is 0, 1, or 2. ##STR4##
A process for preparing the pyrones shown above is claimed in U.S. Pat. No. 3,931,235.